Gene Summary

Gene:ATG5; autophagy related 5
Aliases: ASP, APG5, APG5L, hAPG5, SCAR25, APG5-LIKE
Summary:The protein encoded by this gene, in combination with autophagy protein 12, functions as an E1-like activating enzyme in a ubiquitin-like conjugating system. The encoded protein is involved in several cellular processes, including autophagic vesicle formation, mitochondrial quality control after oxidative damage, negative regulation of the innate antiviral immune response, lymphocyte development and proliferation, MHC II antigen presentation, adipocyte differentiation, and apoptosis. Several transcript variants encoding different protein isoforms have been found for this gene. [provided by RefSeq, Sep 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:autophagy protein 5
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ATG5 (cancer-related)

Cai Q, Wang S, Jin L, et al.
Long non-coding RNA GBCDRlnc1 induces chemoresistance of gallbladder cancer cells by activating autophagy.
Mol Cancer. 2019; 18(1):82 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gallbladder cancer is the most common biliary tract malignancy and not sensitive to chemotherapy. Autophagy is an important factor prolonging the survival of cancer cells under chemotherapeutic stress. We aimed to investigate the role of long non-coding RNAs (lncRNAs) in autophagy and chemoresistance of gallbladder cancer cells.
METHODS: We established doxorubicin (Dox)-resistant gallbladder cancer cells and used microarray analysis to compare the expression profiles of lncRNAs in Dox-resistant gallbladder cancer cells and their parental cells. Knockdown or exogenous expression of lncRNA combined with in vitro and in vivo assays were performed to prove the functional significance of lncRNA. The effects of lncRNA on autophagy were assessed by stubRFP-sensGFP-LC3 and western blot. We used RNA pull-down and mass spectrometry analysis to identify the target proteins of lncRNA.
RESULTS: The drug-resistant property of gallbladder cancer cells is related to their enhanced autophagic activity. And we found a lncRNA ENST00000425894 termed gallbladder cancer drug resistance-associated lncRNA1 (GBCDRlnc1) that serves as a critical regulator in gallbladder cancer chemoresistance. Furthermore, we discovered that GBCDRlnc1 is upregulated in gallbladder cancer tissues. Knockdown of GBCDRlnc1, via inhibiting autophagy at initial stage, enhanced the sensitivity of Dox-resistant gallbladder cancer cells to Dox in vitro and in vivo. Mechanically, we identified that GBCDRlnc1 interacts with phosphoglycerate kinase 1 and inhibits its ubiquitination in Dox-resistant gallbladder cancer cells, which leads to the down-regulation of autophagy initiator ATG5-ATG12 conjugate.
CONCLUSIONS: Our findings established that the chemoresistant driver GBCDRlnc1 might be a candidate therapeutic target for the treatment of advanced gallbladder cancer.

Li N, Fan X, Wang X, et al.
Autophagy-Related 5 Gene rs510432 Polymorphism Is Associated with Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Virus Infection.
Immunol Invest. 2019; 48(4):378-391 [PubMed] Related Publications
BACKGROUND: Despite the identification of autophagy-related protein 5 (ATG5) as a molecule involved in the activated autophagy machinery during hepatitis B virus (HBV) infection and hepatocarcinogenesis, the consequences of ATG5 mutation carriage for patients with chronic HBV infection remain unclear. This study examined the association of ATG5 polymorphisms with HBV-related diseases including hepatocellular carcinoma (HCC).
PATIENTS AND METHODS: Two functionally relevant polymorphisms ATG5 rs573775 and rs510432 were genotyped by ligase detection reaction-polymerase chain reaction in 403 patients with chronic HBV infection (171 chronic hepatitis, 119 cirrhosis and 113 HCC) and 196 healthy controls. Univariate and multivariate logistic regression was performed to evaluate factors associated with HCC.
RESULTS: The rs573775 genotype and allele frequencies had no significant differences between patients with different clinical diseases. However, HCC patients had significantly higher frequency of rs510432 genotype AA (odds ratio [OR] 2.185, 95% confidence interval [CI] 1.042-4.581, P = 0.037, P value by Bonferroni correction [P
CONCLUSION: These results indicate that rs510432 genotypes AA+GA are associated with disease progression and HCC risk in chronic HBV infection, providing novel evidence for a role of ATG5 in the pathogenesis of HBV-related HCC.
ABBREVIATIONS: HBV: hepatitis B virus; HCC hepatocellular carcinoma; TNFSF10: tumor necrosis factor superfamily member 10; ATG5: autophagy-related protein 5; DNA: deoxyribonucleic acid; LDR-PCR: ligase detection reactions-polymerase chain reaction; PCR: polymerase chain reaction; SLE: systemic lupus erythematosus; BD: Behçet's disease; IL-10: interlukin-10; LPS: lipopolysaccharide; PBMC: peripheral blood mononuclear cells; CWP: coal workers' pneumoconiosis; TNF-α: tumor necrosis factor-α.

Zóia MAP, Azevedo FVP, Vecchi L, et al.
Inhibition of Triple-Negative Breast Cancer Cell Aggressiveness by Cathepsin D Blockage: Role of Annexin A1.
Int J Mol Sci. 2019; 20(6) [PubMed] Free Access to Full Article Related Publications
Triple-negative breast cancers (TNBCs) are more aggressive than other breast cancer (BC) subtypes and lack effective therapeutic options. Unraveling marker events of TNBCs may provide new directions for development of strategies for targeted TNBC therapy. Herein, we reported that Annexin A1 (AnxA1) and Cathepsin D (CatD) are highly expressed in MDA-MB-231 (TNBC lineage), compared to MCF-10A and MCF-7. Since the proposed concept was that CatD has protumorigenic activity associated with its ability to cleave AnxA1 (generating a 35.5 KDa fragment), we investigated this mechanism more deeply using the inhibitor of CatD, Pepstatin A (PepA). Fourier Transform Infrared (FTIR) spectroscopy demonstrated that PepA inhibits CatD activity by occupying its active site; the OH bond from PepA interacts with a CO bond from carboxylic acids of CatD catalytic aspartate dyad, favoring the deprotonation of Asp

Xu J, Song J, Yang X, et al.
ProNGF siRNA inhibits cell proliferation and invasion of pancreatic cancer cells and promotes anoikis.
Biomed Pharmacother. 2019; 111:1066-1073 [PubMed] Related Publications
BACKGROUND: Precursor of nerve growth factor (proNGF) was previously considered biologically inactive; however, it has recently been identified as having important roles in the pathology of cancer development.
AIM: This study aimed to explore the therapeutic effects of proNGF siRNA on the proliferation, invasion, and anoikis of pancreatic cancer cells and determine the functions of proNGF.
METHODS: Pancreatic ductal adenocarcinoma (PDAC) and paired paracancerous tissue samples were collected from 60 patients for evaluation of proNGF expression by immunohistochemistry staining, qPCR, and western blotting. PDAC cell proliferation, migration, apoptosis, and anoikis following proNGF siRNA knockdown were investigated in two pancreatic cancer cell lines, Panc-1 and Bxpc-3, using BrdU incorporation assays, EdU staining, Ki-67 immunofluorescence (IF) staining, wound-healing assays, transwell invasion assays, and EthD-1 IF staining. Autophagy-related proteins were also measured by western blotting.
RESULTS: Levels of proNGF protein were higher in pancreatic cancer tissues and cells lines than those in paracancerous tissues and normal pancreatic duct epithelial cells, respectively. In vitro, ProNGF knockdown by siRNA led to significantly reduced cell proliferation, remarkably inhibited wound-healing, and reduced the number of invaded PDAC cells in migration and transwell assays. Treatment with proNGF siRNA also downregulated ATG5 and Beclin 1 protein levels, increased those of P62, and increased EthD-1 staining in PDAC cells.
CONCLUSION: ProNGF expression is elevated in PDAC tissues and cell lines, and proNGF siRNA can inhibit cell proliferation, migration, and invasion, and promote anoikis of pancreatic cancer cells, in which decreased proNGF may participate.

Cherukula K, Uthaman S, Park IK
Design of an Amphiphilic Poly(aspartamide)-mediated Self-assembled Nanoconstruct for Long-Term Tumor Targeting and Bioimaging.
Molecules. 2019; 24(5) [PubMed] Free Access to Full Article Related Publications
Biodegradable polymers have been developed for the targeted delivery of therapeutics to tumors. However, tumor targeting and imaging are usually limited by systemic clearance and non-specific adsorption. In this study, we used poly(amino acid) derivatives, such as poly(succinimide), to synthesize a nanomicelle-forming poly(hydroxyethylaspartamide) (PHEA, P) modified sequentially with octadecylamine, polyethylene glycol (PEG, P), and glycine (G) to design PHEA-PEG-glycine (PPG) nanoparticles (NPs). These PPG NPs were further tethered to cyclic Arg-Gly-Asp (cRGD) sequences for formulating tumor-targeting PPG-cRGD NPs, and then loaded with IR-780 dye (PPG-cRGD-IR-780) for visualizing tumor homing. cRGD cloaked in PPG NPs could bind specifically to both tumor endothelium and cancer cells overexpressing α

Tekedereli I, Akar U, Alpay SN, et al.
Autophagy is Required to Regulate Mitochondria Renewal, Cell Attachment, and All-trans-Retinoic Acid-Induced Differentiation in NB4 Acute Promyelocytic Leukemia Cells.
J Environ Pathol Toxicol Oncol. 2019; 38(1):13-20 [PubMed] Related Publications
All-trans-retinoic acid (ATRA) is a potent inducer of cellular differentiation, growth arrest, and apoptosis as well as a front-line therapy for acute promyelocytic leukemia (APL). The present study provides evidence that induction of autophagy is required for ATRA to induce differentiation of APL (NB4) cells into granulocytes. ATRA treatment causes ~12-fold increase in the number of acidic vesicular organelles and induces marked up-regulation of LC3-II, autophagy-related 5 (ATG5), and Beclin-1. Transmission electron microscopy (TEM) revealed a decrease in mitochondria and ATRA-induced differentiation. To determine the role of autophagy in the differentiation of APL, we knocked down ATG5 in NB4 cells to find that ATRA-induced differentiation is significantly inhibited during ATG5 knock down in cells, indicating the role of autophagy in differentiation of APL. Further experiments revealed restriction of autophagy during ATRA-induced differentiation and inhibition of tissue transglutaminase 2 (TG2) and phospho-focal adhesion kinase (p-FAK), which are known to have roles in differentiation and cell attachment. We examined expression of Beclin-1 and B-cell lymphoma-2 (Bcl-2) and levels of mechanistic target of rapamycin (mTOR) after ATRA treatment. ATRA inhibits Bcl-2, up-regulates Beclin-1 expression, and reduces induction of mTOR activation/phosphorylation in NB4 cells. Our results reveal that autophagy has roles in regulation of differentiation, mitochondria elimination, and cell attachment during ATRA-induced APL differentiation.

Cheng X, Xu Q, Zhang Y, et al.
miR-34a inhibits progression of neuroblastoma by targeting autophagy-related gene 5.
Eur J Pharmacol. 2019; 850:53-63 [PubMed] Related Publications
Neuroblastoma (NB) is a common pediatric malignancy with high mortality in childhood. Although many attentions have been gained, novel biomarkers for NB diagnosis and prognosis are still needed. microRNAs (miRNAs) played important roles in NB progression and miR-34a is a tumor suppressor in NB. However, the mechanism that underlies miR-34a regulating proliferation, migration, invasion and autophagy in NB remains poorly understood. In this study, cell proliferation was investigated by MTT and colony assay. Cell apoptosis was measured by caspase 3 activity assay. Cell migration and invasion were detected by trans-well analysis. Autophagy was measured via GFP-LC3 puncta fluorescence assay and western blots (WB). The expression of miR-34a was examined by quantitative real-time PCR (qRT-PCR). The regulatory effect of miR-34a on autophagy-related gene 5 (ATG5) was detected by qRT-PCR and WB. The interaction between miR-34a and ATG5 was probed by luciferase activity and RNA immunoprecipitation (RIP) assay. Results showed that miR-34a expression was inhibited in NB tissues and cells with low survival rate. Addition of miR-34a suppressed cell proliferation, migration, invasion and autophagy but promoted apoptosis in NB cells, whereas miR-34a deficiency played opposite roles in NB progression. Intriguingly, ATG5 was directly targeted by miR-34a. Moreover, ATG5 restoration attenuated miR-34a-mediated inhibitory effect on proliferation, apoptosis, migration, invasion and autophagy. These results indicated miR-34a suppressed proliferation, apoptosis, migration, invasion and autophagy in NB cells by targeting ATG5, providing a novel therapeutic avenue for NB treatment.

Huang S, Qi P, Zhang T, et al.
The HIF‑1α/miR‑224‑3p/ATG5 axis affects cell mobility and chemosensitivity by regulating hypoxia‑induced protective autophagy in glioblastoma and astrocytoma.
Oncol Rep. 2019; 41(3):1759-1768 [PubMed] Related Publications
Human glioblastoma is a malignant and aggressive primary human brain solid tumor characterized by severe hypoxia. Hypoxia can induce autophagy, which may result in chemoresistance and malignant progression of cancer cells. MicroRNAs (miRNAs) have been reported to modulate hypoxia‑induced autophagy in various types of cancers. In the present study, we observed that hypoxia‑inducible factor (HIF)‑1α expression was increased while miR‑224‑3p expression was decreased under hypoxia in a time‑dependent manner in glioma LN229 and astrocytoma U‑251MG cell lines, as deteced by western blot analysis and real‑time quantitative polymerase chain reaction. In addition, HIF‑1α knockout inhibited cell motility and chemosensitivity by negatively regulating the expression of miR‑224‑3p under a hypoxic condition by Transwell and MTT assay. Moreover, hypoxia increased the relative expression of ATG5 (autophagy‑related gene 5) and LC3 II/I with a decreased level of p62. These results were correlated with autophagy in a time‑dependent manner, suggesting that hypoxia induced autophagy in glioblastoma and astrocytoma cells. Through bioinformatic prediction and luciferase reporter assay, we confirmed that ATG5 is a target of miR‑224‑3p and ATG5 expression was negatively regulated by miR‑224‑3p. Knockdown of ATG5 inhibited cell mobility with increased chemosensitivity of glioblastoma cells under hypoxia. Moreover, overexpression of miR‑224‑3p also inhibited cell mobility with increased chemosensitivity of glioblastoma cells under hypoxia. However, activation of autophagy was able to counteract these effects of miR‑224‑3p. Furthermore, in vivo experiments indicated that the miR‑224‑3p mimic enhanced the chemosensitivity of LN229 cells to temozolomide by immunohistochemistry and TUNEL assay. In summary, our experiments elucidated that the HIF‑1α/miR‑224‑3p/ATG5 axis affects cell mobility and chemosensitivity by regulating hypoxia‑induced autophagy in glioblastoma and astrocytoma. Therefore, miR‑224‑3p could be a novel target against hypoxia‑induced autophagy in glioblastoma and astrocytoma.

Du S, Wang Y, Alatrash N, et al.
Altered profiles and metabolism of l- and d-amino acids in cultured human breast cancer cells vs. non-tumorigenic human breast epithelial cells.
J Pharm Biomed Anal. 2019; 164:421-429 [PubMed] Related Publications
Herein we describe for the first time the endogenous levels of free l-and d-amino acids in cultured human breast cancer cells (MCF-7) and non-tumorigenic human breast epithelial cells (MCF-10A). d-Asp and d-Ser, which are co-agonists of the N-methyl-d-aspartate (NMDA) receptors, showed significantly elevated levels in MCF-7 cancer cells compared to MCF-10A cells. This may result from upregulated enzymatic racemases. Possible roles of these d-amino acids in promoting breast cancer proliferation by regulating NMDA receptors were indicated. d-Asn may also be able to serve as exchange currency, like specific l-amino acids, for the required uptake of essential amino acids and other low abundance nonessential amino acids which were elevated nearly 60 fold in cancer cells. The relative levels of specific l- and d-amino acids can be used as malignancy indicators (MIs) for the breast cancer cell line in this study. High MIs (>50) result from the increased demands of specific essential amino acids. Very low MIs (<1) result from the increased demands of specific d-amino acids (i.e., d-Ser, d-Asp) or the cellular release of amino acid exchange currency (i.e., l- and d-Asn) used in the upregulated amino acid antiporters to promote cancer cell proliferation.

Cirone M
EBV and KSHV Infection Dysregulates Autophagy to Optimize Viral Replication, Prevent Immune Recognition and Promote Tumorigenesis.
Viruses. 2018; 10(11) [PubMed] Free Access to Full Article Related Publications
Autophagy is a catabolic process strongly involved in the immune response, and its dysregulation contributes to the onset of several diseases including cancer. The human oncogenic gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), manipulate autophagy, either during the de novo infection or during the lytic reactivation, in naturally latently-infected lymphoma cells. In particular, the gammaherpesvirus infection reduces autophagy in immune cells, such as monocytes, resulting in the impairment of cell survival and cell differentiation into dendritic cells (DCs), which are essential for initiating and regulating the immune response. In the case of EBV, the reduction of autophagy in these cells, leading to p62 accumulation, activated the p62-NRF2-antioxidant response, reducing ROS, and further inhibiting autophagy. KSHV inhibits autophagy in monocytes by de-phosphorylating JNK2, altering the calpains⁻calpastatin balance and increasing the calpain activity responsible for the cleavage of ATG5. To further impair the immune response, KSHV also inhibits autophagy in differentiated DCs by hyper-phosphorylating STAT3. Conversely, when the lytic cycle is induced in vitro in latently-infected lymphoma B cells, both EBV and KSHV promote autophagy to enhance their replication, although the final autophagic steps are blocked through the down-regulation of Rab7. This strategy allows viruses to avoid the destructive environment of lysosomes, and to exploit the autophagic machinery for intracellular transportation. EBV and KSHV encode for proteins that may either inhibit or promote autophagy and, in addition, they can modulate the cellular pathways that control this process. In this review we will discuss the findings that indicate that autophagy is dysregulated by gammaherpesvirus to promote immune suppression, facilitate viral replication and contribute to the onset and maintenance of gammaherpesvirus-associated malignancies.

Gil J, Ramsey D, Pawlowski P, et al.
The Influence of Tumor Microenvironment on ATG4D Gene Expression in Colorectal Cancer Patients.
Med Oncol. 2018; 35(12):159 [PubMed] Free Access to Full Article Related Publications
Despite great progress in research on the subject, the involvement of autophagy in colorectal cancer (CRC) pathogenesis (initiation, progression, metastasis) remains obscure and controversial. Autophagy is a catabolic process, fundamental to cell viability and connected with degradation/recycling of proteins and organelles. In this study, we aimed at investigating the relative expression level of mRNA via Real-Time PCR of 16 chosen genes belonging to Atg8 mammalian orthologs and their conjugation system, comprising GABARAP, GABARAPL1, GABARAPL2, MAP1LC3A, MAP1LC3B, MAP1LC3C, ATG3, ATG7, ATG10, ATG4A, ATG4B, ATG4C, ATG4D, and three genes encoding proteins building the multimeric ATG16L1 complex, namely ATG5, ATG12, and ATG16L1, in 73 colorectal tumors and paired adjacent normal colon mucosa. Our study demonstrated the relative downregulation of all examined genes in CRC tissues in comparison to adjacent noncancerous mucosa, with the highest rate of expression in both tumor and non-tumor tissues observed for GAPARBPL2 and the lowest for MAP1LC3C. Moreover, in patients with advanced-stage tumors and high values of regional lymph nodes, statistically significant downregulation of ATG4D expression in adjacent normal cells was observed. Our study confirms the role of autophagy genes as cancer suppressors in colorectal carcinogenesis. Furthermore, in regard to the ATG4D gene, we observed the influence of tumor microenvironments on gene expression in adjacent colon mucosa.

Xi Z, Si J, Nan J
LncRNA MALAT1 potentiates autophagy‑associated cisplatin resistance by regulating the microRNA‑30b/autophagy‑related gene 5 axis in gastric cancer.
Int J Oncol. 2019; 54(1):239-248 [PubMed] Related Publications
Gastric cancer (GC) is the fourth most common type of cancer worldwide and chemoresistance is a major obstacle to successful GC treatment. In the present study, reverse transcription‑quantitative polymerase chain reaction analysis was used to measure the expression of metastasis‑associated lung adenocarcinoma transcript 1 (MALAT1) and microRNA (miR)‑30b. Western blot analysis was conducted to detect the protein expression of autophagy‑related gene 5 (ATG5), p62 and LC3 (LC3‑I and LC3‑II). Cell viability and half maximal inhibitory concentration were determined by the Cell Counting Kit‑8 assay. The green fluorescent protein (GFP)‑LC3‑positive cell percentage was determined by the GFP‑LC3 puncta experiment. Luciferase reporter and RNA immunoprecipitation assays were used to explore the molecular associations among MALAT1, miR‑30b and ATG5. MALAT1 was found to be highly expressed in CDDP‑resistant AGS(AGS/CDDP) cells and CDDP‑resistant HGC‑27 (HGC‑27/CDDP) cells. Cell viability was markedly increased in MALAT1‑overexpressing AGS/CDDP cells, but was notably reduced in MALAT1‑depleted HGC‑27/CDDP cells. Moreover, MALAT1 potentiated CDDP resistance by facilitating autophagy in AGS/CDDP and HGC‑27/CDDP cells. Further investigations demonstrated that MALAT1 inhibited miR‑30b expression by direct interaction. Moreover, miR‑30b abolished MALAT1‑induced CDDP resistance by inhibiting autophagy in AGS/CDDP and HGC‑27/CDDP cells. Furthermore, ATG5 was found to be a target of miR‑30b. miR‑30b weakened resistance to CDDP by inhibiting autophagy in AGS/CDDP and HGC‑27/CDDP cells, while this effect was abrogated by increased ATG5 expression. Additionally, MALAT1 sequestered miR‑30b from ATG5 to increase ATG5 expression in AGS/CDDP and HGC‑27/CDDP cells. Therefore, MALAT1 potentiated autophagy‑related CDDP resistance through suppressing the miR‑30b/ATG5 axis in AGS/CDDP and HGC‑27/CDDP cells, indicating that it may represent a promising target for the reversal of chemoresistance in GC.

Mansouri Bidkani M, Tabatabaeian H, Parsafar S, et al.
ErbB4 receptor polymorphism 2368A>C and risk of breast cancer.
Breast. 2018; 42:157-163 [PubMed] Related Publications
PURPOSE: A number of single nucleotide polymorphisms (SNPs) in EebB4 gene have been studied, which has clarified their impact on breast cancer in different populations. Nevertheless, the importance of rs13423759 in breast cancer has not been studied and its effect remained almost unclear. In this paper, we evaluated the frequency of rs13423759 different alleles in Iranian population and statistically analyzed their association with breast cancer risk.
MATERIALS AND METHODS: Allele-specific Primer PCR (ASP-PCR) was recruited in this study to genotype rs13423759 position in 172 breast cancer and 148 healthy control subjects. The genotypes of control and cases were analyzed statistically to find the association between rs13423759 alleles and breast cancer incidence and its clinicopathological characteristics. In silico studies were performed in order to find the mechanistic viewpoint of rs13423759 alleles in breast cancer.
RESULTS: rs13423759 allele C was shown to be significantly associated with breast cancer risk, HER2 positivity and increased risk of metastasis. Reciprocally, allele A was correlated with the lowered risk of breast cancer. The in silico studies showed that rs13423759 allele C is capable to strengthen the interaction between miR-548as, an oncomiRNA, and ErbB4 mRNA, leading to its lowered concentration in the cells.
CONCLUSION: rs13423759 allele C is significantly associated with the enhanced risk of breast cancer, elevated metastasis and HER2 positivity.

Santoni M, Piva F, De Giorgi U, et al.
Autophagic Gene Polymorphisms in Liquid Biopsies and Outcome of Patients with Metastatic Clear Cell Renal Cell Carcinoma.
Anticancer Res. 2018; 38(10):5773-5782 [PubMed] Related Publications
BACKGROUND/AIM: Autophagy has been shown to be involved in cancer development and response to cancer therapy. In this study, genotypes of autophagic genes were analyzed to assess their correlation with the risk of clear cell renal cell carcinoma (ccRCC) and the outcome of patients treated with pazopanib for metastatic ccRCC.
MATERIALS AND METHODS: Single nucleotide polymorphisms (SNPs)were selected in the following genes: ATG4A (rs7880351), ATG4B (rs6709768), ATG4C (rs2886770, rs6670694, rs6683832), ATG5 (rs9373839, rs3804333, rs490010), ATG16L1 (rs6752107), ATG16L2 (rs10751215) and IRGM (rs10059011). The Kaplan-Meier method and log-rank test were used to evaluate differences between groups.
RESULTS: Forty patients with metastatic ccRCC treated with pazopanib were included in the analysis. ATG16L2rs10751215 was significantly less frequent in patients with ccRCC compared to the general population, suggesting its potential protective role, while ATG4Ars7880351, ATG4C rs6670694 and rs6683832 and ATG5 rs490010 were correlated with the progression-free survival (PFS) of patients treated with pazopanib.
CONCLUSION: Our results suggest, for the first time, that autophagic gene SNPs are associated with ccRCC risk and patient outcome.

Batool S, Joseph TP, Hussain M, et al.
LP1 from
Int J Mol Sci. 2018; 19(10) [PubMed] Free Access to Full Article Related Publications
Present study aimed to elucidate the anticancer effect and the possible molecular mechanism underlying the action of Latcripin 1 (LP1), from the mushroom

Shang HS, Lu HF, Lee CH, et al.
Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells.
Environ Toxicol. 2018; 33(11):1168-1181 [PubMed] Related Publications
Quercetin is one of the natural components from natural plant and it induces cell apoptosis in many human cancer cell lines. However, no available reports show that quercetin induces apoptosis and altered associated gene expressions in human gastric cancer cells, thus, we investigated the effect of quercetin on the apoptotic cell death and associated gene expression in human gastric cancer AGS cells. Results indicated that quercetin induced cell morphological changes and reduced total viability via apoptotic cell death in AGS cells. Furthermore, results from flow cytometric assay indicated that quercetin increased reactive oxygen species (ROS) production, decreased the levels of mitochondrial membrane potential (ΔΨ

Kim JC, Ha YJ, Tak KH, et al.
Opposite functions of GSN and OAS2 on colorectal cancer metastasis, mediating perineural and lymphovascular invasion, respectively.
PLoS One. 2018; 13(8):e0202856 [PubMed] Free Access to Full Article Related Publications
The present study aimed to identify molecules associated with lymphovascular invasion (LVI) and perineural invasion (PNI) and to examine their biological behavior in colorectal cancer (CRC). LVI- and PNI-associated molecules were identified and verified using sequential processes including (1) identification of 117 recurrence-associated genes differentially expressed on RNA-seq analysis using primary cancer tissues from 130 CRC patients with and without systemic recurrence; (2) analysis of molecules associated with LVI and PNI; (3) assessment of biological properties by measuring proliferation, anoikis, invasion/migration, epithelial-mesenchymal transition and autophagy flux; and (4) verification of disease-free survival using public datasets. Gelsolin (GSN) and 2'-5'-oligoadenylate synthetase 2 (OAS2) were associated with PNI and LVI, respectively. Invasion potential was >2-fold greater in GSN-overexpressing LoVo cells than in control cells (p<0.001-0.005), whereas OAS2-overexpressing RKO cells showed reduced invasion (p<0.001-0.005). GSN downregulated E-cadherin, β-catenin, claudin-1 and snail, and upregulated N-cadherin and ZEB1, whereas OAS2 overexpression had the opposite effects. Several autophagy-related proteins including ATG5-12, ATG6/BECN1, ATG7 and ATG101 were downregulated in GSN-overexpressing LoVo cells, whereas the opposite pattern was observed in OAS2-overexpressing RKO cells. Patients with low GSN expression had significantly higher 5-year recurrence-free survival (RFS) rates than those with GSN overexpression (73.6% vs. 64.7%, p = 0.038), whereas RFS was longer in patients with OAS2 overexpression than in those with underexpression (73.4% vs. 63.7%, p = 0.01). In conclusion, GSN and OAS2 were positively and negatively associated with recurrence, respectively, suggesting their potential value as predictors of recurrence or therapeutic targets in CRC patients.

Xu J, Patel NH, Saleh T, et al.
Differential Radiation Sensitivity in p53 Wild-Type and p53-Deficient Tumor Cells Associated with Senescence but not Apoptosis or (Nonprotective) Autophagy.
Radiat Res. 2018; 190(5):538-557 [PubMed] Related Publications
Studies of radiation interaction with tumor cells often focus on apoptosis as an end point; however, clinically relevant doses of radiation also promote autophagy and senescence. Moreover, functional p53 has frequently been implicated in contributing to radiation sensitivity through the facilitation of apoptosis. To address the involvement of apoptosis, autophagy, senescence and p53 status in the response to radiation, the current studies utilized isogenic H460 non-small cell lung cancer cells that were either p53-wild type (H460wt) or null (H460crp53). As anticipated, radiosensitivity was higher in the H460wt cells than in the H460crp53 cell line; however, this differential radiation sensitivity did not appear to be a consequence of apoptosis. Furthermore, radiosensitivity did not appear to be reduced in association with the promotion of autophagy, as autophagy was markedly higher in the H460wt cells. Despite radiosensitization by chloroquine in the H460wt cells, the radiation-induced autophagy proved to be essentially nonprotective, as inhibition of autophagy via 3-methyl adenine (3-MA), bafilomycin A1 or ATG5 silencing failed to alter radiation sensitivity or promote apoptosis in either the H460wt or H460crp53 cells. Radiosensitivity appeared to be most closely associated with senescence, which occurred earlier and to a greater extent in the H460wt cells. This finding is consistent with the in-depth proteomics analysis on the secretomes from the H460wt and H460crp53 cells (with or without radiation exposure) that showed no significant association with radioresistance-related proteins, whereas several senescence-associated secretory phenotype (SASP) factors were upregulated in H460wt cells relative to H460crp53 cells. Taken together, these findings indicate that senescence, rather than apoptosis, plays a central role in determination of radiosensitivity; furthermore, autophagy is likely to have minimal influence on radiosensitivity under conditions where autophagy takes the nonprotective form.

Ji X, Bossé Y, Landi MT, et al.
Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.
Nat Commun. 2018; 9(1):3221 [PubMed] Free Access to Full Article Related Publications
Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

Zhao GS, Gao ZR, Zhang Q, et al.
TSSC3 promotes autophagy via inactivating the Src-mediated PI3K/Akt/mTOR pathway to suppress tumorigenesis and metastasis in osteosarcoma, and predicts a favorable prognosis.
J Exp Clin Cancer Res. 2018; 37(1):188 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Over the last two or three decades, the pace of development of treatments for osteosarcoma tends has been slow. Novel effective therapies for osteosarcoma are still lacking. Previously, we reported that tumor-suppressing STF cDNA 3 (TSSC3) functions as an imprinted tumor suppressor gene in osteosarcoma; however, the underlying mechanism by which TSSC3 suppresses the tumorigenesis and metastasis remain unclear.
METHODS: We investigated the dynamic expression patterns of TSSC3 and autophagy-related proteins (autophagy related 5 (ATG5) and P62) in 33 human benign bone tumors and 58 osteosarcoma tissues using immunohistochemistry. We further investigated the correlations between TSSC3 and autophagy in osteosarcoma using western blotting and transmission electronic microscopy. CCK-8, Edu, and clone formation assays; wound healing and Transwell assays; PCR; immunohistochemistry; immunofluorescence; and western blotting were used to investigated the responses in TSSC3-overexpressing osteosarcoma cell lines, and in xenografts and metastasis in vivo models, with or without autophagy deficiency caused by chloroquine or ATG5 silencing.
RESULTS: We found that ATG5 expression correlated positively with TSSC3 expression in human osteosarcoma tissues. We demonstrated that TSSC3 was an independent prognostic marker for overall survival in osteosarcoma, and positive ATG5 expression associated with positive TSSC3 expression suggested a favorable prognosis for patients. Then, we showed that TSSC3 overexpression enhanced autophagy via inactivating the Src-mediated PI3K/Akt/mTOR pathway in osteosarcoma. Further results suggested autophagy contributed to TSSC3-induced suppression of tumorigenesis and metastasis in osteosarcoma in vitro and in vivo models.
CONCLUSIONS: Our findings highlighted, for the first time, the importance of autophagy as an underlying mechanism in TSSC3-induced antitumor effects in osteosarcoma. We also revealed that TSSC3-associated positive ATG5 expression might be a potential predictor of favorable prognosis in patients with osteosarcoma.

Powers N, Srivastava A
The Air Sac Primordium of
Int J Mol Sci. 2018; 19(7) [PubMed] Free Access to Full Article Related Publications
The acquisition of invasive properties preceding tumor metastasis is critical for cancer progression. This phenomenon may result from mutagenic disruption of typical cell function, but recent evidence suggests that cancer cells frequently co-opt normal developmental programs to facilitate invasion as well. The signaling cascades that have been implicated present an obstacle to identifying effective therapeutic targets because of their complex nature and modulatory capacity through crosstalk with other pathways. Substantial efforts have been made to study invasive behavior during organogenesis in several organisms, but another model found in

Vu HT, Kobayashi M, Hegazy AM, et al.
Autophagy inhibition synergizes with calcium mobilization to achieve efficient therapy of malignant gliomas.
Cancer Sci. 2018; 109(8):2497-2508 [PubMed] Free Access to Full Article Related Publications
Autophagy plays a critical role in tumorigenesis, but how autophagy contributes to cancer cells' responses to chemotherapeutics remains controversial. To investigate the roles of autophagy in malignant gliomas, we used CRISPR/CAS9 to knock out the ATG5 gene, which is essential for autophagosome formation, in tumor cells derived from patients with glioblastoma. While ATG5 disruption inhibited autophagy, it did not change the phenotypes of glioma cells and did not alter their sensitivity to temozolomide, an agent used for glioblastoma patient therapy. Screening of an anticancer drug library identified compounds that showed greater efficacy to ATG5-knockout glioma cells compared to control. While several selected compounds, including nigericin and salinomycin, remarkably induced autophagy, potent autophagy inducers by mTOR inhibition did not exhibit the ATG5-dependent cytoprotective effects. Nigericin in combination with ATG5 deficiency synergistically suppressed spheroid formation by glioma cells in a manner mitigated by Ca

Gu Z, Hou Z, Zheng L, et al.
LncRNA DICER1-AS1 promotes the proliferation, invasion and autophagy of osteosarcoma cells via miR-30b/ATG5.
Biomed Pharmacother. 2018; 104:110-118 [PubMed] Related Publications
Osteosarcoma is a prevalent primary malignant tumor and long non-coding RNAs (lncRNAs) have been validated to modulate the osteosarcoma tumorigenesis. In present study, our research team investigates the role of a novel identified lncRNA DICER1-AS1 on the tumor progression and autophagy. Results showed that lncRNA DICER1-AS1 was up-regulated in osteosarcoma cells using microarray analysis and RT-PCR. Cellular functional experiments revealed that DICER1-AS1 knockdown suppressed the proliferation, migration, invasion and autophagy of osteosarcoma cells in vitro. Besides, DICER1-AS1 knockdown inhibited the protein expression levels of ATG5, LC3-II and Beclin 1, suggesting the inhibition on the autophagy of osteosarcoma cells. Moreover, miR-30b was verified to target 3'-UTR of DICER1-AS1 and ATG5 using bioinformatics tools and luciferase reporter assay or RNA-immunoprecipitation (RIP). Western blot showed that ATG5 protein expression was decreased in DICER1-AS1 knockdown and miR-30b mimics transfected cells, while increased in miR-30b inhibitor transfected cells, presenting a negative correlation with miR-30b and a positive correlation with DICER1-AS1. Finally, xenograft assay in vivo indicated that DICER1-AS1 knockdown inhibited the osteosarcoma tumor growth and protein expression level of ATG5. In summary, all the results conclude that DICER1-AS1 regulates the proliferation, invasion and autophagy of osteosarcoma via miR-30b/ATG5 axis, providing a novel insight for osteosarcoma tumorigenesis.

Talukdar S, Pradhan AK, Bhoopathi P, et al.
MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells.
Proc Natl Acad Sci U S A. 2018; 115(22):5768-5773 [PubMed] Free Access to Full Article Related Publications
Glioma stem cells (GSCs) comprise a small subpopulation of glioblastoma multiforme cells that contribute to therapy resistance, poor prognosis, and tumor recurrence. Protective autophagy promotes resistance of GSCs to anoikis, a form of programmed cell death occurring when anchorage-dependent cells detach from the extracellular matrix. In nonadherent conditions, GSCs display protective autophagy and anoikis-resistance, which correlates with expression of melanoma differentiation associated gene-9/Syntenin (MDA-9) (syndecan binding protein; SDCBP). When MDA-9 is suppressed, GSCs undergo autophagic death supporting the hypothesis that MDA-9 regulates protective autophagy in GSCs under anoikis conditions. MDA-9 maintains protective autophagy through phosphorylation of BCL2 and by suppressing high levels of autophagy through EGFR signaling. MDA-9 promotes these changes by modifying FAK and PKC signaling. Gain-of-function and loss-of-function genetic approaches demonstrate that MDA-9 regulates pEGFR and pBCL2 expression through FAK and pPKC. EGFR signaling inhibits autophagy markers (ATG5, Lamp1, LC3B), helping to maintain protective autophagy, and along with pBCL2 maintain survival of GSCs. In the absence of MDA-9, this protective mechanism is deregulated; EGFR no longer maintains protective autophagy, leading to highly elevated and sustained levels of autophagy and consequently decreased cell survival. In addition, pBCL2 is down-regulated in the absence of MDA-9, leading to cell death in GSCs under conditions of anoikis. Our studies confirm a functional link between MDA-9 expression and protective autophagy in GSCs and show that inhibition of MDA-9 reverses protective autophagy and induces anoikis and cell death in GSCs.

Jin J, Britschgi A, Schläfli AM, et al.
Low Autophagy (ATG) Gene Expression Is Associated with an Immature AML Blast Cell Phenotype and Can Be Restored during AML Differentiation Therapy.
Oxid Med Cell Longev. 2018; 2018:1482795 [PubMed] Free Access to Full Article Related Publications
Autophagy is an intracellular degradation system that ensures a dynamic recycling of a variety of building blocks required for self-renewal, homeostasis, and cell survival under stress. We used primary acute myeloid leukemia (AML) samples and human AML cell lines to investigate the regulatory mechanisms of autophagy and its role in AML differentiation. We found a significantly lower expression of key autophagy- (ATG-) related genes in primary AML as compared to healthy granulocytes, an increased autophagic activity during all-

Yang J, Pi C, Wang G
Inhibition of PI3K/Akt/mTOR pathway by apigenin induces apoptosis and autophagy in hepatocellular carcinoma cells.
Biomed Pharmacother. 2018; 103:699-707 [PubMed] Related Publications
Apigenin is a dietary flavonoid with known antioxidant and antitumor effects against several types of cancers by promoting cell death and inducing cell cycle arrest. Apigenin also regulates a variety of intracellular signal transduction pathways during apoptosis or autophagy. However, the precise mechanism underlying the anticancer effects of apigenin in liver cancer remains poorly understood. In this study, we demonstrated that apigenin has anticancer activity against hepatocellular carcinoma cells. Apigenin inhibited the cell growth and induced cell death in a dose- and time-dependent manner in HepG2 cells. We found that apigenin treatment increased the expression of LC3-II and the number of GFP-LC3 puncta. Moreover, inhibition of autophagy with 3-MA and Atg5 gene silencing strengthened apigenin-induced proliferation inhibition and apoptosis. Our data has indicated that apigenin-induced autophagy has a protective effect against cell death. Additionally, apigenin induced apoptosis and autophagy through inhibition of PI3K/Akt/mTOR pathway. Most importantly, in vivo data showed that administration of apigenin decreased tumor growth and autophagy inhibition by 3-MA significantly enhanced the anticancer effect of apigenin. Collectively, our results reveal that apigenin inhibits cell proliferation and induces autophagy via suppressing the PI3K/Akt/mTOR pathway. Our results also suggest combination of autophagy inhibitors and apigenin would be a potential chemotherapeutic strategy against hepatocellular carcinoma.

Cramer DW, Fichorova RN, Terry KL, et al.
Anti-CA15.3 and Anti-CA125 Antibodies and Ovarian Cancer Risk: Results from the EPIC Cohort.
Cancer Epidemiol Biomarkers Prev. 2018; 27(7):790-804 [PubMed] Free Access to Full Article Related Publications

Song X, Yuan Z, Yuan H, et al.
ATG12 expression quantitative trait loci associated with head and neck squamous cell carcinoma risk in a Chinese Han population.
Mol Carcinog. 2018; 57(8):1030-1037 [PubMed] Related Publications
Autophagy is an essential process to maintain cellular homeostasis and functions, which has been demonstrated to play an important role in the different stages of tumorigenesis. To evaluate whether the genetic variants in autophagy-related genes influence the head and neck squamous cell carcinoma (HNSCC) risk, we conducted a case-control study to analyze 11 tagging single nucleotide polymorphisms (SNPs) of three core autophagosome formation genes (ATG5, ATG12, and ATG16L1) with 576 HNSCC cases and 1552 healthy controls among Chinese population. Finally, we identified that rs26537 of ATG12 (additive model: adjusted odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.03-1.37, P = 0.017) and rs4663402 in ATG16L1 (additive model: adjusted OR = 1.39, 95%CI = 1.08-1.80, P = 0.010) were significantly associated with the increased risk of HNSCC. However, no association was detected between other SNPs and HNSCC risk. The results of expression quantitative trait loci (eQTL) analysis based on Genotype-Tissue Expression (GTEx) accessible data, showed that the risk allele of rs26537 was significantly associated with up-regulated expression of ATG12 (P = 0.0021). Further luciferase activity assay indicated that rs26537 T > C in ATG12 intron one region significantly enhanced transcription activity. These results suggested that ATG12 eQTL SNP rs26537 might contribute to an allele-specific effect on the expression of host gene ATG12 and explain a fraction of HNSCC genetic susceptibility.

Ayesh BM, Al-Masri R, Abed AA
CHRNA5 and CHRNA3 polymorphism and lung cancer susceptibility in Palestinian population.
BMC Res Notes. 2018; 11(1):218 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The genetic polymorphism (rs16969968 in CHRNA5, and rs1051730 in CHRNA3 genes) were recently shown to be associated with risk of LC. The aim of this study is to elucidate whether they predispose Palestinian individuals to lung cancer, and how is this related to smoking.
RESULTS: Frequency of the rs16969968-A allele was significantly higher in the case group (36.7%) than in normal controls (17.5%; P = 0.022; OR = 6.83 for AA and 2.81 for AG genotypes). The frequency of rs1051730-T allele was also significantly higher in the case group (46.7%) than in the control group (22.5%; P = 0.001; OR = 2.20 for TC and 13.22 for TT genotypes). Frequency of rs16969968-A allele was higher in smokers (29.1%) than nonsmokers (15.7%) regardless of lung cancer; similarly, frequency of rs1051730-T allele was also higher in smokers than in smokers (46.7% vs 22.5%, respectively). The higher the proportion of the risk allele (rs16969968-A and rs1051730-T), the higher the mean number of daily consumed cigarettes (P = 0.006). Carrying rs16969968-A and/or rs1051730-T alleles results in an increased risk to lung cancer probably by increasing the individual's tendency for heavy smoking. The allelic frequency of the rs16969968-A and rs1051730-T alleles among normal Palestinian controls is similar to different populations worldwide.

Tsai TC, Lai KH, Su JH, et al.
7-Acetylsinumaximol B Induces Apoptosis and Autophagy in Human Gastric Carcinoma Cells through Mitochondria Dysfunction and Activation of the PERK/eIF2α/ATF4/CHOP Signaling Pathway.
Mar Drugs. 2018; 16(4) [PubMed] Free Access to Full Article Related Publications
The 7-Acetylsinumaximol B (7-AB), a bioactive cembranoid, was originally discovered from aquaculture soft coral

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